1. Field of the Invention
The present invention relates to a process for the optical resolution of optically active substituted benzylamines and the adduct salt of the substituted benzylamine and an N-acyl-amino acid formed in the separation.
2. Discussion of the Background
Optically active substituted benzylamines are important materials as optical resolving agents to obtain optically active isomers from racemic carboxylic acids. In particular, .alpha.-arylalkylamines comprising a phenyl group and methyl or ethyl group are frequently used as optical resolving agents. S or R amines in which the aryl groups are derived from a variety of aromatic compounds are also, important raw materials for potent sweetener compounds, comprising aspartyl dipeptide derivatives represented by the formula (2) below and their salts, EQU L--Asp--X--NH--C*HR.sup.1 R.sup.2 ( 2)
wherein, R.sup.1 represents C.sub.1-6 alkyl or C.sub.2-7 alkoxymethyl; R.sup.2 represents phenyl, benzyl, cyclohexyl, or cyclohexyl-methyl; structures containing C* have an (S) configuration if the R.sup.1 is an alkyl group and (R) configuration if R.sup.1 is an alkoxymethyl group. If R, is alkyl, X represents D-norleucine, D-leucine, D-isoleucine, D-alloisoleucine, D-threonine, D-0-methyl-threonine, D-allothreonine, D-0-methylallothreonine, D- or DL-furylglycine or a similar D-.alpha.-amino acid residue or a DL-.alpha.-amino acid residue, or a C.sub.3-6 cyclic or acyclic .alpha.,.alpha.-dialkyl amino acid residue; if R.sup.1 is an alkoxymethyl group, X represents D-alanine, D-.alpha.-amino butyric acid, D-norvaline, D-valine, D-norleucine, D-leucine, D-isoleucine, D-alloisoleucine, D-t-leucine, D-serine, D-0-methylserine, D-threonine, D-0-methylthreonine, D-allothreonine, D-0-methyl allothreonine, D-phenylglycine, D- or DL-furylglycine or a similar D-.alpha.-amino acid residue or DL-.alpha. amino acid residue, or a C.sub.3-6 cyclic or acyclic .alpha.,.alpha.-dialkyl amino acid residue. L--Asp and X are bonded via an .alpha.-bonding. These potent sweeteners also include aspartyl dipeptide amide derivatives represented by the general formula (3) below and their salts EQU L--Asp--X--NH--C*HR.sup.1 R.sup.2 ( 3)
wherein, X represents D-alanine, D-.alpha.-amino butyric acid, D-norvaline, D-valine, D-norleucine, D-leucine, D-isoleucine, D-alloisoleucine, D-t-leucine, D-serine, D-0-methylserine, D-threonine, D-0-methylthreonine, D-allothreonine, D-0-methylallothreonine, D-phenylglycine, D-or DL-furylglycine or a similar D-.alpha.-amino acid residue or DL-.alpha.-amino acid residue, or a C.sub.3-6 cyclic or acyclic .alpha.,.alpha.-dialkyl amino acid residue; R.sup.1 represents a C.sub.1-6 alkyl group or C.sub.2-7 alkoxymethyl group; R.sup.2 represents a phenyl group having a substituent in the 2-, 3-, or 4- position selected from the group containing F, Cl, Br, I, hydroxy, C.sub.1-6 alkoxy, cyano, nitro, acetyl, amino, and acetyl amino, or a phenyl group having a 2, 3- or 3, 4-methylenedioxy, trimethylene, or tetramethylene substituent; or 2, 3, or 4-pyridyl, 2- or 3-furyl, or 2- or 3-thienyl substituent; structures containing C* are (S) or (RS) isomers if R.sup.1 is alkyl; or they represent (R), (S), or (RS) if R.sup.1 is alkoxymethyl; and the L--Asp is bonded to X via an .alpha.-bonding.
Aspartyl dipeptides of formula (2) include .alpha.-L-aspartyl-D-threonine (S)-.alpha.-ethylbenzylamide; .alpha.-L-aspartyl-DL-furylglycine (S)-.alpha.-ethylbenzylamide; .alpha.-aspartyl-DL-furylglycine (S)-.alpha.-methoxymethylbenzylamide; .alpha.-L-aspartyl-.alpha.-aminocyclopentanecarboxylic acid (S)-.alpha.-ethylbenzylamide; .alpha.-L-aspartyl-aminocyclohexanecarboxylic acid (S)-.alpha.-ethylbenzylamide; .alpha.-L-aspartyl-D-valine (R)-.alpha.-methoxymethylbenzylamide; .alpha.-L-aspartyl- D-.alpha.-aminobutyric acid (R)-.alpha.-methoxymethylbenzylamide; and the like: Japanese Patent Application H7-42818.
Aspartyl dipeptide amides of formula (3) include .alpha.-L-aspartyl-D-.alpha.-aminobutyric acid (S)-.alpha.-ethyl-p-hydroxybenzylamide; .alpha.-L-aspartyl-D-.alpha.-aminobutyric acid (R)-methoxymethyl-p-hydroxybenzylamide; .alpha.-L-aspartyl- D-valine (S)-.alpha.-ethyl-p-hydroxybenzylamide; .alpha.-L-aspartyl-D-valine-(R)-.alpha.-methoxymethyl-p-hydroxybenzylamide ; .alpha.-L-aspartyl-D-valine (S)-.alpha.-ethyl-p-chlorobenzylamide, and the like: Japanese Patent Application H7-144844.
Conventional methods for obtaining optically active substituted benzylamines from their racemic isomers by optical resolution generally call for forming salts with various optically active carboxylic acids and separating the two diastereomer salts generated by taking advantage of the difference in the solubilities. Methods are known in the art, for example, including a method which uses optically active tartaric acid or malic acid (J. Chem. Soc., 1940, 336), a method of using optically active N-acetyl-3,5-dibromo-tyrosine (J. Am. Chem. Soc., 73, 5782 (1951)), and a method of using optically active 2-benzamide cyclohexane carboxylic acid (Bull. Chem. Soc. Jpn., 61, 1395 (1988)).
However, methods in which tartaric acid and malic acids are used are low in optical refining efficiency, often requiring recrystallizing and refining the resultant diastereomer salts multiple times. Although tartaric acid and malic acid are relatively low in cost, they are difficult to efficiently recover in this resolution process, which is a problem for commercialization.
In the method using optically active N-acetyl-3,5-dibromo-tyrosine, the preparation of this material itself is cumbersome and provides only insufficient optical refining capability.
The use of optically active 2-benzamide-cyclohexane carboxylic acids often gives high optical purity amines in a single crystallization, but the crystallization yield is not very high. In addition this material is relatively expensive.
Thus, while these known resolving agents are excellent on a laboratory scale, all suffer from some problem when used in industrial scale.